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1. Identification of pathogenic gene variants in small families with intellectually disabled siblings by exome sequencing.

Author

Schuurs-Hoeijmakers JH, Vulto-van Silfhout AT, Vissers LE, van de Vondervoort II, van Bon BW, de Ligt J, Gilissen C, Hehir-Kwa JY, Neveling K, del Rosario M, Hira G, Reitano S, Vitello A, Failla P, Greco D, Fichera M, Galesi O, Kleefstra T, Greally MT, Ockeloen CW, Willemsen MH, Bongers EM, Janssen IM, Pfundt R, Veltman JA, Romano C, Willemsen MA, van Bokhoven H, Brunner HG, de Vries BB, and de Brouwer AP

Subjects
DNA Mutational Analysis, Family, Female, Humans, Male, Pedigree, Exome genetics, Intellectual Disability genetics, Mutation genetics
Abstract

Background: Intellectual disability (ID) is a common neurodevelopmental disorder affecting 1-3% of the general population. Mutations in more than 10% of all human genes are considered to be involved in this disorder, although the majority of these genes are still unknown., Objectives: We investigated 19 small non-consanguineous families with two to five affected siblings in order to identify pathogenic gene variants in known, novel and potential ID candidate genes. Non-consanguineous families have been largely ignored in gene identification studies as small family size precludes prior mapping of the genetic defect., Methods and Results: Using exome sequencing, we identified pathogenic mutations in three genes, DDHD2, SLC6A8, and SLC9A6, of which the latter two have previously been implicated in X-linked ID phenotypes. In addition, we identified potentially pathogenic mutations in BCORL1 on the X-chromosome and in MCM3AP, PTPRT, SYNE1, and ZNF528 on autosomes., Conclusions: We show that potentially pathogenic gene variants can be identified in small, non-consanguineous families with as few as two affected siblings, thus emphasising their value in the identification of syndromic and non-syndromic ID genes.

Published
2013
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2. Familial 1.1 Mb deletion in chromosome Xq22.1 associated with mental retardation and behavioural disorders in female patients.

Author

Grillo L, Reitano S, Belfiore G, Spalletta A, Amata S, Bottitta M, Barone C, Falco M, Fichera M, and Romano C

Subjects
Child, Comparative Genomic Hybridization, Female, Humans, Microsatellite Repeats genetics, Multigene Family, Muscle Hypotonia genetics, Nucleocytoplasmic Transport Proteins genetics, Phenotype, RNA, Messenger metabolism, RNA-Binding Proteins genetics, Chromosome Deletion, Chromosomes, Human, X, Intellectual Disability genetics, Mental Disorders genetics
Abstract

We report on a 7-year-old girl with severe mental retardation (MR), autism, micro-brachycephaly, generalized muscle hypotonia with distal hypotrophy of lower limbs, scoliosis and facial dysmorphisms. Array-CGH analysis identified a 1.1 Mb deletion of chromosome Xq22.1. Further analysis demonstrated that the deletion was inherited from her mother who showed mild MR, short stature, brachycephaly, epilepsy and a Borderline Personality Disorder. Microsatellite segregation analysis revealed that the rearrangement arose de novo in the mother on the paternal X chromosome. The deleted Xq22.1 region contains part of the NXF gene cluster which is involved in mRNA nuclear export and metabolism. Among them, the NXF5 gene has already been linked to mental retardation whereas NXF2 protein has been recently found to be partner of FMRP in regulating Nxf1 mRNA stability in neuronal cells. The dosage imbalance of NXF5 and NXF2 genes may explain the severe phenotype in our patient., (Copyright 2010 Elsevier Masson SAS. All rights reserved.)

Published
2010
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3. The 2q23.1 microdeletion syndrome: clinical and behavioural phenotype.

Author

van Bon BW, Koolen DA, Brueton L, McMullan D, Lichtenbelt KD, Adès LC, Peters G, Gibson K, Moloney S, Novara F, Pramparo T, Dalla Bernardina B, Zoccante L, Balottin U, Piazza F, Pecile V, Gasparini P, Guerci V, Kets M, Pfundt R, de Brouwer AP, Veltman JA, de Leeuw N, Wilson M, Antony J, Reitano S, Luciano D, Fichera M, Romano C, Brunner HG, Zuffardi O, and de Vries BB

Subjects
Angelman Syndrome genetics, Cesarean Section, Child, Chromosome Mapping, Female, Humans, Infant, Newborn, Intensive Care Units, Neonatal, Learning Disabilities genetics, Male, Phenotype, Rett Syndrome genetics, Chromosomes, Human, Pair 2 genetics, Intellectual Disability genetics, Sequence Deletion
Abstract

Six submicroscopic deletions comprising chromosome band 2q23.1 in patients with severe mental retardation (MR), short stature, microcephaly and epilepsy have been reported, suggesting that haploinsufficiency of one or more genes in the 2q23.1 region might be responsible for the common phenotypic features in these patients. In this study, we report the molecular and clinical characterisation of nine new 2q23.1 deletion patients and a clinical update on two previously reported patients. All patients were mentally retarded with pronounced speech delay and additional abnormalities including short stature, seizures, microcephaly and coarse facies. The majority of cases presented with stereotypic repetitive behaviour, a disturbed sleep pattern and a broad-based gait. These features led to the initial clinical impression of Angelman, Rett or Smith-Magenis syndromes in several patients. The overlapping 2q23.1 deletion region in all 15 patients comprises only one gene, namely, MBD5. Interestingly, MBD5 is a member of the methyl CpG-binding domain protein family, which also comprises MECP2, mutated in Rett's syndrome. Another gene in the 2q23.1 region, EPC2, was deleted in 12 patients who had a broader phenotype than those with a deletion of MBD5 only. EPC2 is a member of the polycomb protein family, involved in heterochromatin formation and might be involved in causing MR. Patients with a 2q23.1 microdeletion present with a variable phenotype and the diagnosis should be considered in mentally retarded children with coarse facies, seizures, disturbed sleeping patterns and additional specific behavioural problems.

Published
2010
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4. Complex segmental duplications mediate a recurrent dup(X)(p11.22-p11.23) associated with mental retardation, speech delay, and EEG anomalies in males and females.

Author

Giorda R, Bonaglia MC, Beri S, Fichera M, Novara F, Magini P, Urquhart J, Sharkey FH, Zucca C, Grasso R, Marelli S, Castiglia L, Di Benedetto D, Musumeci SA, Vitello GA, Failla P, Reitano S, Avola E, Bisulli F, Tinuper P, Mastrangelo M, Fiocchi I, Spaccini L, Torniero C, Fontana E, Lynch SA, Clayton-Smith J, Black G, Jonveaux P, Leheup B, Seri M, Romano C, dalla Bernardina B, and Zuffardi O

Subjects
Female, Humans, Male, Pedigree, Chromosomes, Human, X genetics, Electroencephalography, Gene Duplication, Intellectual Disability complications, Intellectual Disability genetics, Language Development Disorders complications, Language Development Disorders genetics
Abstract

Submicroscopic copy-number variations make a considerable contribution to the genetic etiology of human disease. We have analyzed subjects with idiopathic mental retardation (MR) by using whole-genome oligonucleotide-based array comparative genomic hybridization (aCGH) and identified familial and de novo recurrent Xp11.22-p11.23 duplications in males and females with MR, speech delay, and a peculiar electroencephalographic (EEG) pattern in childhood. The size of the duplications ranges from 0.8-9.2 Mb. Most affected females show preferential activation of the duplicated X chromosome. Carriers of the smallest duplication show X-linked recessive inheritance. All other affected individuals present dominant expression and comparable clinical phenotypes irrespective of sex, duplication size, and X-inactivation pattern. The majority of the rearrangements are mediated by recombination between flanking complex segmental duplications. The identification of common clinical features, including the typical EEG pattern, predisposing genomic structure, and peculiar X-inactivation pattern, suggests that duplication of Xp11.22-p11.23 constitutes a previously undescribed syndrome.

Published
2009
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5. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes.

Author

Mefford HC, Sharp AJ, Baker C, Itsara A, Jiang Z, Buysse K, Huang S, Maloney VK, Crolla JA, Baralle D, Collins A, Mercer C, Norga K, de Ravel T, Devriendt K, Bongers EM, de Leeuw N, Reardon W, Gimelli S, Bena F, Hennekam RC, Male A, Gaunt L, Clayton-Smith J, Simonic I, Park SM, Mehta SG, Nik-Zainal S, Woods CG, Firth HV, Parkin G, Fichera M, Reitano S, Lo Giudice M, Li KE, Casuga I, Broomer A, Conrad B, Schwerzmann M, Räber L, Gallati S, Striano P, Coppola A, Tolmie JL, Tobias ES, Lilley C, Armengol L, Spysschaert Y, Verloo P, De Coene A, Goossens L, Mortier G, Speleman F, van Binsbergen E, Nelen MR, Hochstenbach R, Poot M, Gallagher L, Gill M, McClellan J, King MC, Regan R, Skinner C, Stevenson RE, Antonarakis SE, Chen C, Estivill X, Menten B, Gimelli G, Gribble S, Schwartz S, Sutcliffe JS, Walsh T, Knight SJ, Sebat J, Romano C, Schwartz CE, Veltman JA, de Vries BB, Vermeesch JR, Barber JC, Willatt L, Tassabehji M, and Eichler EE

Subjects
Cataract congenital, Cataract genetics, Child, Chromosome Deletion, Female, Gene Duplication, Gene Rearrangement, Genetic Variation, Heart Defects, Congenital genetics, Humans, Male, Microcephaly genetics, Phenotype, Recombination, Genetic, Autistic Disorder genetics, Chromosome Aberrations, Chromosomes, Human, Pair 1 genetics, Congenital Abnormalities genetics, Intellectual Disability genetics
Abstract

Background: Duplications and deletions in the human genome can cause disease or predispose persons to disease. Advances in technologies to detect these changes allow for the routine identification of submicroscopic imbalances in large numbers of patients., Methods: We tested for the presence of microdeletions and microduplications at a specific region of chromosome 1q21.1 in two groups of patients with unexplained mental retardation, autism, or congenital anomalies and in unaffected persons., Results: We identified 25 persons with a recurrent 1.35-Mb deletion within 1q21.1 from screening 5218 patients. The microdeletions had arisen de novo in eight patients, were inherited from a mildly affected parent in three patients, were inherited from an apparently unaffected parent in six patients, and were of unknown inheritance in eight patients. The deletion was absent in a series of 4737 control persons (P=1.1x10(-7)). We found considerable variability in the level of phenotypic expression of the microdeletion; phenotypes included mild-to-moderate mental retardation, microcephaly, cardiac abnormalities, and cataracts. The reciprocal duplication was enriched in nine children with mental retardation or autism spectrum disorder and other variable features (P=0.02). We identified three deletions and three duplications of the 1q21.1 region in an independent sample of 788 patients with mental retardation and congenital anomalies., Conclusions: We have identified recurrent molecular lesions that elude syndromic classification and whose disease manifestations must be considered in a broader context of development as opposed to being assigned to a specific disease. Clinical diagnosis in patients with these lesions may be most readily achieved on the basis of genotype rather than phenotype., (2008 Massachusetts Medical Society)

Published
2008
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6. The 2q23.1 microdeletion syndrome: clinical and behavioural phenotype

Author

Bon, B.W.M. van, Koolen, D.A., Brueton, L., McMullan, D., Lichtenbelt, K.D., Ades, L.C., Peters, G., Gibson, K., Moloney, S., Novara, F., Pramparo, T., Bernardina, B. Dalla, Zoccante, L., Balottin, U., Piazza, F., Pecile, V., Gasparini, P., Guerci, V., Kets, M., Pfundt, R., Brouwer, A.P.M. de, Veltman, J.A., Leeuw, N. de, Wilson, M., Antony, J., Reitano, S., Luciano, D., Fichera, M., Romano, C, Brunner, H.G., Zuffardi, O., Vries, L.B.A. de, VAN BON, Bw, Koolen, Da, Brueton, L, Mcmullan, D, Lichtenbelt, Kd, Adès, Lc, Peters, G, Gibson, K, Novara, F, Pramparo, T, Bernardina, Bd, Zoccante, L, Balottin, U, Piazza, F, Pecile, V, Gasparini, Paolo, Guerci, V, Kets, M, Pfundt, R, DE BROUWER, Ap, Veltman, Ja, DE LEEUW, N, Wilson, M, Antony, J, Reitano, S, Luciano, D, Fichera, M, Romano, C, Brunner, Hg, Zuffardi, O, and DE VRIES, Bb

Subjects
Male, Microcephaly, Genetics and epigenetic pathways of disease [NCMLS 6], 2q23.1 microdeletion syndrome, Rett syndrome, phenotype, behaviour, Short stature, Article, MECP2, Genomic disorders and inherited multi-system disorders [IGMD 3], Intellectual Disability, Intensive Care Units, Neonatal, Angelman syndrome, Rett Syndrome, Genetics, Humans, Medicine, Child, Genetics (clinical), Sequence Deletion, Cesarean Section, Learning Disabilities, business.industry, Infant, Newborn, Chromosome Mapping, Microdeletion syndrome, medicine.disease, Phenotype, Chromosomes, Human, Pair 2, Speech delay, Female, Angelman Syndrome, medicine.symptom, Corrigendum, business, Haploinsufficiency
Abstract

Contains fulltext : 89008.pdf (Publisher’s version ) (Closed access) Six submicroscopic deletions comprising chromosome band 2q23.1 in patients with severe mental retardation (MR), short stature, microcephaly and epilepsy have been reported, suggesting that haploinsufficiency of one or more genes in the 2q23.1 region might be responsible for the common phenotypic features in these patients. In this study, we report the molecular and clinical characterisation of nine new 2q23.1 deletion patients and a clinical update on two previously reported patients. All patients were mentally retarded with pronounced speech delay and additional abnormalities including short stature, seizures, microcephaly and coarse facies. The majority of cases presented with stereotypic repetitive behaviour, a disturbed sleep pattern and a broad-based gait. These features led to the initial clinical impression of Angelman, Rett or Smith-Magenis syndromes in several patients. The overlapping 2q23.1 deletion region in all 15 patients comprises only one gene, namely, MBD5. Interestingly, MBD5 is a member of the methyl CpG-binding domain protein family, which also comprises MECP2, mutated in Rett's syndrome. Another gene in the 2q23.1 region, EPC2, was deleted in 12 patients who had a broader phenotype than those with a deletion of MBD5 only. EPC2 is a member of the polycomb protein family, involved in heterochromatin formation and might be involved in causing MR. Patients with a 2q23.1 microdeletion present with a variable phenotype and the diagnosis should be considered in mentally retarded children with coarse facies, seizures, disturbed sleeping patterns and additional specific behavioural problems. 01 februari 2010

Published
2009

7. Definition of the neurological phenotype associated with dup (X) (p11.22-p11.23)

Author

Corrado Romano, Roberto Giorda, Girolamo Aurelio Vitello, Maria Savio, Massimo Mastrangelo, M. Broli, Roberto Poda, B. Bernardi, Francesca Bisulli, Santina Reitano, Roberto Gallassi, Marco Seri, Orsetta Zuffardi, Isabella Fiocchi, Claudio Zucca, Paolo Tinuper, Elena Fontana, Sebastiano A. Musumeci, Maria Clara Bonaglia, Daniela Cevolani, Bernardo Dalla Bernardina, Raffaele Agati, Serafino Buono, Broli M., Bisulli F., Mastrangelo M., Fontana E., Fiocchi I., Zucca C., Bonaglia M.C., Buono S., Musumeci S.A., Romano C., Reitano S., Savio M., Vitello G.A., Bernardi B., Cevolani D., Agati R., Poda R., Gallassi R., Giorda R., Zuffardi O., Bernardina B.D., Seri M., and Tinuper P.

Subjects
Adult, Male, Xp11.2211.23, medicine.medical_specialty, Pediatrics, Neurology, Adolescent, Gene Dosage, Neural Conduction, speech impairment, Neurological examination, Status epilepticus, Electroencephalography, Neuropsychological Tests, mental retardation, Gene Duplication, Intellectual Disability, medicine, Humans, Neuropsychological assessment, Child, In Situ Hybridization, Fluorescence, Chromosomes, Human, X, medicine.diagnostic_test, Electrodiagnosis, Neuropsychology, Brain, Magnetic resonance imaging, General Medicine, Magnetic Resonance Imaging, Phenotype, Speech delay, Female, Neurology (clinical), medicine.symptom, Nervous System Diseases, Psychology, Neuroscience
Abstract

The aim of this study was to describe in detail the neurological features of nine patients carrying the recently reported microduplication at Xp11.22-11.23. Clinical and neurological examination, brain magnetic resonance imaging (except for two patients), electroencephalography and a neuropsychological assessment specific for language disturbances were performed in nine patients with microduplication at Xp11.22-11.23, disclosed by comparative genomic hybridisation array. Six patients were familial cases belonging to three unrelated pedigrees and three were sporadic cases. The patients had the following characteristics: mild dysmorphic facial features (except for two patients), mental retardation with moderate to severe global language deterioration, electroencephalographic epileptiform discharges during wakefulness and especially during sleep or electrical status epilepticus during slow sleep in younger cases, and negative brain magnetic resonance imaging. The main clinical features of this new microduplication syndrome were mild facial dysmorphisms, from increased electroencephalogram abnormalities during sleep to electrical status epilepticus during slow sleep, and mental retardation mainly involving language function in the absence of detectable brain lesions. In the absence of detectable brain lesions, speech delay may be associated with electrical status epilepticus during slow sleep or, alternatively, related to abnormal brain expression of a dosage-sensitive gene contained within the duplication region.

Published
2011

8. Complex Segmental Duplications Mediate a Recurrent dup(X)(p11.22-p11.23) Associated with Mental Retardation, Speech Delay, and EEG Anomalies in Males and Females

Author

Sebastiano A. Musumeci, Freddie H. Sharkey, Roberto Giorda, Orsetta Zuffardi, Isabella Fiocchi, Bruno Leheup, Luigina Spaccini, M. Clara Bonaglia, Graeme C.M. Black, Massimo Mastrangelo, Elena Fontana, Jill Clayton-Smith, Susan Marelli, Francesca Novara, Daniela Di Benedetto, Marco Seri, Sally Ann Lynch, Emanuela Avola, Claudio Zucca, Paolo Tinuper, Girolamo Aurelio Vitello, Rita Grasso, Marco Fichera, Philippe Jonveaux, Pinella Failla, Silvana Beri, Claudia Torniero, Lucia Castiglia, Bernardo Dalla Bernardina, Pamela Magini, Jill E. Urquhart, Francesca Bisulli, Corrado Romano, Santina Reitano, Giorda R., Bonaglia M.C., Beri S., Fichera M., Novara F., Magini P., Urquhart J., Sharkey F.H., Zucca C., Grasso R., Marelli S., Castiglia L., Di Benedetto D., Musumeci S.A., Vitello G.A., Failla P., Reitano S., Avola E., Bisulli F., Tinuper P., Mastrangelo M., Fiocchi I., Spaccini L., Torniero C., Fontana E., Lynch S.A., Clayton-Smith J., Black G., Jonveaux P., Leheup B., Seri M., Romano C., dalla Bernardina B., and Zuffardi O.

Subjects
Male, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Audiology, Electroencephalography, Biology, mental retardation, 03 medical and health sciences, 0302 clinical medicine, Report, Gene Duplication, Intellectual Disability, dup(X)(p11.22-p11.23), EEG anomalies, Gene duplication, Genetics, medicine, Humans, Genetics(clinical), Language Development Disorders, Genetics (clinical), X chromosome, 030304 developmental biology, Segmental duplication, Chromosomes, Human, X, 0303 health sciences, medicine.diagnostic_test, 030305 genetics & heredity, medicine.disease, Pedigree, Developmental disorder, Speech delay, dup, Female, medicine.symptom, Erratum, 030217 neurology & neurosurgery, Comparative genomic hybridization
Abstract

Submicroscopic copy-number variations make a considerable contribution to the genetic etiology of human disease. We have analyzed subjects with idiopathic mental retardation (MR) by using whole-genome oligonucleotide-based array comparative genomic hybridization (aCGH) and identified familial and de novo recurrent Xp11.22-p11.23 duplications in males and females with MR, speech delay, and a peculiar electroencephalographic (EEG) pattern in childhood. The size of the duplications ranges from 0.8-9.2 Mb. Most affected females show preferential activation of the duplicated X chromosome. Carriers of the smallest duplication show X-linked recessive inheritance. All other affected individuals present dominant expression and comparable clinical phenotypes irrespective of sex, duplication size, and X-inactivation pattern. The majority of the rearrangements are mediated by recombination between flanking complex segmental duplications. The identification of common clinical features, including the typical EEG pattern, predisposing genomic structure, and peculiar X-inactivation pattern, suggests that duplication of Xp11.22-p11.23 constitutes a previously undescribed syndrome.

Published
2009

9. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes

Author

Xavier Estivill, Charles E. Schwartz, Louise Gallagher, Karen Buysse, Soo Mi Park, Iris Casuga, Stefania Gimelli, Regina Regan, Zhaoshi Jiang, Carl Baker, Pasquale Striano, Heather C Mefford, Patrick Verloo, Joris A. Veltman, Giorgio Gimelli, Edward S. Tobias, Sabina Gallati, Jon McClellan, Corrado Romano, Chris Lilley, Kelly Li, Samantha J. L. Knight, Joris Vermeesch, William Reardon, Markus Schwerzmann, Roger E. Stevenson, Koenraad Norga, Martin Poot, Geert Mortier, Yves Spysschaert, Ellen van Binsbergen, Evan E. Eichler, Koenraad Devriendt, Lorraine Gaunt, Bernard Conrad, Lluís Armengol, Stuart Schwartz, Catherine Mercer, John Tolmie, Viv K. Maloney, Lionel Willatt, Antonietta Coppola, Santina Reitano, Susan M. Gribble, John C. K. Barber, Anja De Coene, Frank Speleman, Frédérique Béna, Andy Itsara, Ron Hochstenbach, Caifu Chen, Linde Goossens, Adam Broomer, Tom Walsh, John A. Crolla, Shuwen Huang, Thomy de Ravel, May Tassabehji, Helen V. Firth, Cindy Skinner, Amanda L. Collins, Ernie M.H.F. Bongers, Stylianos E. Antonarakis, Diana Baralle, Michael Gill, Bert B.A. de Vries, Mary Claire King, Jill Clayton-Smith, Nicole de Leeuw, Georgina Parkin, Serena Nik-Zainal, Jonathan Sebat, James S. Sutcliffe, Ingrid Simonic, Björn Menten, Mariangela Lo Giudice, Marco Fichera, Lorenz Räber, Raoul C.M. Hennekam, Sarju G. Mehta, Andrew J. Sharp, Alison Male, Marcel R. Nelen, C. Geoffrey Woods, Mefford, H., Sharp, A., Baker, C., Itsara, A., Jiang, Z., Buysse, K., Huang, S., Maloney, V., Crolla, J., Baralle, D., Collins, A., Mercer, C., Norga, K., De Ravel, T., Devriendt, K., Bongers, E., De Leeuw, N., Reardon, W., Gimelli, S., Bena, F., Hennekam, R., Male, A., Gaunt, L., Clayton-Smith, J., Simonic, I., Park, S., Mehta, S., Nik-Zainal, S., Woods, C., Firth, H., Parkin, G., Fichera, M., Reitano, S., Lo Giudice, M., Li, K., Casuga, I., Broomer, A., Conrad, B., Schwerzmann, M., Räber, L., Gallati, S., Striano, P., Coppola, A., Tolmie, J., Tobias, E., Lilley, C., Armengol, L., Spysschaert, Y., Verloo, P., De Coene, A., Goossens, L., Mortier, G., Speleman, F., Van Binsbergen, E., Nelen, M., Hochstenbach, R., Poot, M., Gallagher, L., Gill, M., Mcclellan, J., King, M. -C., Regan, R., Skinner, C., Stevenson, R., Antonarakis, S., Chen, C., Estivill, X., Menten, B., Gimelli, G., Gribble, S., Schwartz, S., Sutcliffe, J., Walsh, T., Knight, S., Sebat, J., Romano, C., Schwartz, C., Veltman, J., De Vries, B., Vermeesch, J., Barber, J., Willatt, L., Tassabehji, M., Eichler, E., Gimelli, Stefania, Conrad, Bernard, Antonarakis, Stylianos, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, Paediatric Genetics, and University of Groningen

Subjects
Male, Microcephaly, Genetics and epigenetic pathways of disease [NCMLS 6], Congenital, Microcephaly/genetics, 0302 clinical medicine, Gene Duplication, Gene duplication, HUMAN GENOME, genetics, ddc:576.5, Copy-number variation, Child, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), Heart Defects, Renal disorder [IGMD 9], Psychiatry, Gene Rearrangement, Recombination, Genetic, Genetics, 0303 health sciences, General Medicine, Microdeletion syndrome, Chromosomes, Human, Pair 1/ genetics, Heart Defects, Congenital/genetics, 3. Good health, Phenotype, Chromosomes, Human, Pair 1, Autism spectrum disorder, congenital/genetics, Pair 1, Female, Chromosome Deletion, Functional Neurogenomics [DCN 2], Human, Heart Defects, Congenital, SEGMENTAL DUPLICATIONS, MICRODELETION SYNDROME, Context (language use), COPY-NUMBER VARIATION, Chromosomes, Article, Cataract, Congenital Abnormalities, Genomic disorders and inherited multi-system disorders [IGMD 3], 03 medical and health sciences, Genetic, Translational research [ONCOL 3], Intellectual Disability, medicine, Humans, 22Q11.2 DELETION SYNDROME, Autistic Disorder, 030304 developmental biology, Congenital Abnormalities/ genetics, Chromosome Aberrations, Hereditary cancer and cancer-related syndromes [ONCOL 1], business.industry, Genetic Variation, Autistic Disorder/ genetics, Gene rearrangement, medicine.disease, Recombination, Cataract/congenital/genetics, POLYMORPHISM, INDIVIDUALS, Genetic defects of metabolism [UMCN 5.1], ATRIAL-FIBRILLATION, Autism, genetics, Cataract, congenital/genetics, Child, Chromosome Aberrations, Chromosome Deletion, Chromosomes, genetics, Congenital Abnormalities, genetics, Female, Gene Duplication, Gene Rearrangement, Genetic Variation, Heart Defects, genetics, Humans, Intellectual Disability, genetics, Male, Microcephaly, genetics, Phenotype, Recombination, Mental Retardation/ genetics, business, MENTAL-RETARDATION, ARRAY-CGH, 030217 neurology & neurosurgery, Immunity, infection and tissue repair [NCMLS 1]
Abstract

PUBLISHED, Background Duplications and deletions in the human genome can cause disease or predispose persons to disease. Advances in technologies to detect these changes allow for the routine identification of submicroscopic imbalances in large numbers of patients. Methods We tested for the presence of microdeletions and microduplications at a specific region of chromosome 1q21.1 in two groups of patients with unexplained mental retardation, autism, or congenital anomalies and in unaffected persons. Results We identified 25 persons with a recurrent 1.35-Mb deletion within 1q21.1 from screening 5218 patients. The microdeletions had arisen de novo in eight patients, were inherited from a mildly affected parent in three patients, were inherited from an apparently unaffected parent in six patients, and were of unknown inheritance in eight patients. The deletion was absent in a series of 4737 control persons (P=1.1x10?7). We found considerable variability in the level of phenotypic expression of the microdeletion; phenotypes included mild-to-moderate mental retardation, microcephaly, cardiac abnormalities, and cataracts. The reciprocal duplication was enriched in nine children with mental retardation or autism spectrum disorder and other variable features (P=0.02). We identified three deletions and three duplications of the 1q21.1 region in an independent sample of 788 patients with mental retardation and congenital anomalies. Conclusions We have identified recurrent molecular lesions that elude syndromic classification and whose disease manifestations must be considered in a broader context of development as opposed to being assigned to a specific disease. Clinical diagnosis in patients with these lesions may be most readily achieved on the basis of genotype rather than phenotype., Supported in part by grants from the National Institutes of Health (NIH) (HD043569, to Dr. Eichler), the South Carolina Department of Disabilities and Special Needs (to Drs. Skinner, Stevenson, and Schwartz), the Wellcome Trust (061183, to Dr. Tassabehji), the Andre & Cyprien Foundation and the University Hospitals of Geneva (to Drs. Antonarakis, Bena, and Gallati), and the European Union (EU) (project 219250, to Dr. Sharp; AnEUploidy project 037627, to Drs. Leeuw, Armengol, Antonarakis, Estivill, Veltman, and de Vries). The Irish Autism Study was funded by the Wellcome Trust and the Health Research Board (a grant to Drs. Gallagher and Gill). Dr. Poot was supported by a grant from the Dutch Foundation for Brain Research (Hersenstichting grant 2008(1) 34); Drs. Regan and Knight, by the Oxford Partnership Comprehensive Biomedical Research Centre; Dr. Willatt, by the Cambridge Biomedical Research Centre, with funding from the United Kingdom Department of Health's National Institute for Health Research Biomedical Research Centres funding scheme; Drs. Huang and Maloney, as part of the National Genetics Reference Laboratory (Wessex) by the United Kingdom Department of Health; Ms. Buysse, as a research assistant of the Research Foundation?Flanders (FWO?Vlaanderen); and Dr. Eichler, as an investigator of the Howard Hughes Medical Institute.

Published
2008

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